Nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) and their effects on signaling in the nucleus accumbens (NAc) are important for the behavioral actions of nicotine related to addiction. Our hypothesis is that there is a dissociation between nicotine reward and locomotor activation. We hypothesize that nicotine reward necessitates activation of D1 receptors and increased CREB activity in the NAc shell, whereas DA receptor activation in the NAc core is sufficient for locomotor activation, and CREB activity is not necessary. We have used transgenic mice with expression of the beta2-subunit of the nAChR on VTA neurons that project to the NAc core to test the idea that these receptors are sufficient for nicotine-dependent locomotor activation. Preliminary studies show that these mice show relatively normal nicotine-dependent locomotor activation but do not show a place preference for nicotine or activation of CREB in the NAc core. Aim 1 of this project will be to determine whether CREB activity in the NAc shell, but not core, is critical for nicotine reward using viral-mediated gene transfer and complementary pharmacological approaches. In addition we will determine whether the balance between D1 vs. D2 signaling is important for CREB activity in the NAc shell or core, and nicotine reward. Aim 2 will determine whether DA release in the NAc core and not the shell is sufficient for nicotine-mediated locomotor activation, and determine the subsequent effects on CREB activation in the NAc. These experiments are significant because they could explain the very sharp dose-response function for nicotine reward and may provide new points of intervention to support smoking cessation. They will help identify the molecular mechanisms and signaling pathways involved in nicotine locomotion and reward, and determine the role of D1 and D2 receptor activation in these behaviors. These studies will test the hypothesis that CREB activity in the NAc shell integrates D1 and D2 signaling and is a critical output underlying nicotine reward. PUBLIC HEALTH RELEVANCE We know that nicotine is the primary agent in tobacco that leads to addiction. Nicotine changes the strength of communication between nerve cells and this is thought to be responsible for the long-term changes in behavior that results from smoking, including long-lasting increases in cigarette craving and the likelihood to relapse. We have shown that activity of CREB, a molecule that is known to be important for changing the connections between nerve cells, is necessary for nicotine to be rewarding in mice. We have also shown using genetically-manipulated mice that nicotine receptors on a group of nerve cells in the brain's reward center that communicate with what is called the core of the nucleus accumbens are sufficient for the ability of nicotine to act as a stimulant, but not nicotine reward. We believe that nicotine receptors on nerve cells that communicate with the nucleus accumbens shell are important for nicotine reward, whereas nicotine receptors on nerve cells that communicate with the nucleus accumbens core are important for nicotine's stimulant properties. These two pathways can be distinguished genetically, but may also be sensitive to different drugs. We propose that targeting the molecules that lead to long- lasting changes in the communication between nerve cells in the nucleus accumbens shell could lead to new therapies for smoking cessation.